Condensed Ring Pyridine Compounds As Subtype-Selective Modulators Of Sphingosine-1-Phosphate-2 (S1P2) Receptors

ABSTRACT

The invention provides compounds represented by the formula I, each of which compounds may have sphingosine-1-phosphate receptor agonist and or antagonist biological activity, wherein these compounds selected from the group consisting of wherein A, B, C, D, X, Y, Z and R 3  are defined in the specification. Said compounds are useful for treating a disease or condition of a mammal selected from the group consisting of ocular diseases; systemic vascular barrier related diseases; allergies and other inflammatory diseases; cardiac diseases or conditions; fibrosis; pain and wounds.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention claims priority under 35 U.S.C. 119(e) to U.S.Provisional Application No. 61/246,642, filed on Sep. 29, 2009 which isexpressly incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to derivatives and/or analogues ofsphingosine which are useful as anti-fibrotic drugs and are therebyuseful for treating ocular, cardiac, hepatic and pulmonary fibrosis,proliferative vitreoretinopathy, cicatricial pemphigoid, surgicallyinduced fibrosis in cornea, conjunctiva and tenon and for the treatmentof eye diseases and conditions.

2. Summary of the Art

Sphingosine is a compound having the chemical structure shown in thegeneral formula described below, in which Y¹ is hydrogen. It is knownthat various sphingolipids, having sphingosine as a constituent, arewidely distributed in the living body including on the surface of cellmembranes of cells in the nervous system.

A sphingolipid is one of the lipids having important roles in the livingbody. A disease called lipidosis is caused by accumulation of aspecified sphingolipid in the body. Sphingolipids present on cellmembranes function to regulate cell growth; participate in thedevelopment and differentiation of cells; function in nerves; areinvolved in the infection and malignancy of cells; etc. Many of thephysiological roles of sphingolipids remain to be solved. Recently thepossibility that ceramide, a derivative of sphingosine, has an importantrole in the mechanism of cell signal transduction has been indicated,and studies about its effect on apoptosis and cell cycle have beenreported.

Sphingosine-1-phosphate is an important cellular metabolite, derivedfrom ceramide that is synthesized de novo or as part of thesphingomeyeline cycle (in animals cells). It has also been found ininsects, yeasts and plants.

The enzyme, ceramidase, acts upon ceramides to release sphingosine,which is phosphorylated by sphingosine kinase, a ubiquitous enzyme inthe cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate.The reverse reaction can occur also by the action of sphingosinephosphatases, and the enzymes act in concert to control the cellularconcentrations of the metabolite, which concentrations are always low.In plasma, such concentration can reach 0.2 to 0.9 μM, and themetabolite is found in association with the lipoproteins, especially theHDL. It should also be noted that sphingosine-1-phosphate formation isan essential step in the catabolism of sphingoid bases.

Like its precursors, sphingosine-1-phosphate is a potent messengermolecule that perhaps uniquely operates both intra- andinter-cellularly, but with very different functions from ceramides andsphingosine. The balance between these various sphingolipid metabolitesmay be important for health. For example, within the cell,sphingosine-1-phosphate promotes cellular division (mitosis) as opposedto cell death (apoptosis), which it inhibits. Intracellularly, it alsofunctions to regulate calcium mobilization and cell growth in responseto a variety of extracellular stimuli. Current opinion appears tosuggest that the balance between sphingosine-1-phosphate and ceramideand/or sphingosine levels in cells is critical for their viability. Incommon with the lysophospholipids, especially lysophosphatidic acid,with which it has some structural similarities, sphingosine-1-phosphateexerts many of its extra-cellular effects through interaction with fivespecific G protein-coupled receptors on cell surfaces. These areimportant for the growth of new blood vessels, vascular maturation,cardiac development and immunity, and for directed cell movement.

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular disease.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

Fungi and plants have sphingolipids and the major sphingosine containedin these organisms has the formula described below. It is known thatthese lipids have important roles in the cell growth of fungi andplants, but details of the roles remain to be solved.

Recently it has been known that derivatives of sphingolipids and theirrelated compounds exhibit a variety of biological activities throughinhibition or stimulation of the metabolism pathways. These compoundsinclude inhibitors of protein kinase C, inducers of apoptosis,immuno-suppressive compounds, antifungal compounds, and the like.Substances having these biological activities are expected to be usefulcompounds for various diseases.

Derivatives of sphingosine have been prepared in various patents. Forexample, see U.S. Pat. Nos. 4,952,683; 5,110,987; 6,235,912 B1 and6,239,297 B1.

Also, compounds which are similar to certain sphingosine derivatives,but which are not reported as being ligands for the sphingosinereceptors are reported in various patents and published patentapplications. See for example, U.S. Pat. Nos. 5,294,722; 5,102,901;5,403,851 and 5,580,878. U.S. Patent Application Publication No. U.S.2003/0125371 A2.

SUMMARY OF THE INVENTION

The present invention provides compounds that are able to regulate thefunctions of sphingolipid, and pharmaceutical compositions comprisingsaid compounds.

In one aspect of the present invention there are disclosed compounds,having sphingosine-1-phosphate receptor agonist and or antagonistbiological activity, represented by the formula I:

wherein:

wherein A is a direct bond or (CR) and B, C and D are independentlyselected from the group consisting of (CR) and N, wherein R is H oralkyl, e.g. lower alkyl; provided however, not all, of B, C and D are Nand, when A is a direct bond, D is (CR);

R³ is selected from the group consisting of alkyl, e.g. lower alkyl:

X is selected from the group consisting of O, NR⁴ and CR⁴R⁵, wherein R⁴and R⁵ are independently selected from the group consisting of H andalkyl, e.g. lower alkyl;

Y is selected from the group consisting of O or S; and

Z is a substituted aryl ring and pharmaceutically acceptable saltsthereof.

In a first aspect of the present invention, the left most ring is a sixmembered ring, i.e. the compounds of this invention are benzo or pyridopyridinyl compounds. The compounds included in this first aspect of theinvention may be represented by the general formula II, below:

wherein R¹ and R² are independently selected from the group consistingof H and alkyl, e.g. lower alkyl, and may include from 1 to 10 carbons,and may be cyclic or branched chain alkyl radicals having from 3 to 10carbons; methoxy, hydroxyl, halogen, nitrile, trifluoromethyl andcarboxy;

R³ is selected from the group consisting of alkyl, e.g. lower alkyl, andmay include from 1 to 10 carbons, and may be cyclic or branched chainalkyl radicals having from 3 to 10 carbons; methoxy, hydroxyl, halogen,nitrile, trifluoromethyl and carboxy;

D is CR or N;

X is O, NR⁴ or CR⁴R⁵, where R⁴, R⁵ are independently selected from thegroup consisting of H and alkyl, e.g. lower alkyl and may have from 1 to10 carbons, and may be cyclic or branched chain alkyl having 3 to 10carbons, methoxy, hydroxyl, F, Br, I, nitrile, trifluoromethyl andcarboxy;

Y is O or S, preferably O;

Z is a substituted aryl ring, e.g. a carbocyclic or heterocyclic arylring, having the following structure:

wherein R⁶ and R⁷ are independently selected from the group consistingof alkyl and may include from 1 to 10 carbons, and may be cyclic orbranched chain alkyl having 3 to 10 carbons, alkyloxy, preferably loweralkyloxy, e.g. ethyloxy, isopropyloxy, n-butyloxy; hydroxyl, halogen,preferably chloro; nitrile, trifluoromethyl, and carboxy; and

E is N or CR, preferably N

In a second aspect, of the present invention, the compounds of thisinvention the left most ring is a five membered ring, i.e. the compoundsare 1-H pyrazolo[4,3-b]pyridinyl compounds. The compounds included inthis second aspect of the invention may be represented by the generalformula III:

wherein R¹, R²and R³ are independently selected from the groupconsisting of H and alkyl, e.g. lower alkyl, and may include from 1 to10 carbons, and may be cyclic or branched chain alkyl radicals havingfrom 3 to 10 carbons; methoxy, hydroxyl, halogen, nitrile,trifluoromethyl and carboxy;

R³ is selected from the group consisting of alkyl, e.g. lower alkyl, andmay include from 1 to 10 carbons, and may be cyclic or branched chainalkyl radicals having from 3 to 10 carbons; methoxy, hydroxyl, halogen,nitrile, trifluoromethyl and carboxy;

D is CR or N;

X is O, NR⁴, or CR⁴R⁵, where R⁴, R⁵ are independently selected from thegroup consisting of H and alkyl, e.g. lower alkyl and may have from 1 to10 carbons, and may be cyclic or branched chain alkyl having 3 to 10carbons, methoxy, hydroxyl, F, Br, I, nitrile, trifluoromethyl andcarboxy;

Y is O or S, preferably O;

Z is a substituted aryl ring, e.g. a carbocyclic or heterocyclic arylring, having the following structure:

wherein R⁶ and R⁷ are independently selected from the group consistingof alkyl and may include from 1 to 10 carbons, and may be cyclic orbranched chain alkyl having 3 to 10 carbons, alkyloxy, preferably loweralkyloxy, e.g. ethyloxy, isopropyloxy, n-butyloxy; hydroxyl, halogen,preferably chloro; nitrile, trifluoromethyl, and carboxy; and

E is N or CR, preferably N;

Preferably, Z is a disubstituted aryl, more preferably ano,o-substituted pyridinyl.

In another aspect of this invention, there is disclosed a method oftreating or preventing a disease or condition selected from the groupconsisting of fibrotic conditions e.g.; ocular, cardiac, hepatic andpulmonary fibrosis, proliferative vitreoretinopathy, cicatricialpemphigoid, surgically induced fibrosis in cornea, conjunctiva and tenonwhich comprises administering to a patient in need thereof a compoundrepresented by the formula I, II, or III, above.

DETAILED DESCRIPTION OF THE INVENTION

Novel compounds having this general structure were synthesized andtested for sphingosine 2-phosphate receptor activity using the FLIPRassay. Cells expressing the receptor of interest (S1P₁, S1P₂ or S1P₃)and a G-protein (Gqi5 or G16) are loaded with fluo-4, a calciumsensitive dye. After removal of excess dye by washing, the cells areplaced in the FLIPR TETRA instrument. Baseline fluorescence readings aretaken prior to addition the compound to be tested. Agonists will triggerthe receptor to interact with the G-protein, leading to an increase inintracellular calcium. The increase in intracellular calcium causes anincrease in the fluorescence of the cells, due to the presence offluo-4. This fluorescence increase is recorded by the FLIPR TETRA. Afterthe calcium transient signal has decreased towards baseline, thestandard agonist sphingosine 1-phosphate is added. If the test compoundis an antagonist, an initial calcium signal will not be generated andthe antagonist will prevent the generation of a calcium signal fromsphingosine 1-phosphate. The level of fluorescence is compared to thatof sphingosine 1-phosphate, and the EC50 or IC50 of the compounddetermined by curve fitting.

The compounds in this invention are useful for the treatment of mammals,including humans, for diseases or conditions selected from the groupconsisting of ocular, cardiac, hepatic and pulmonary fibrosis,proliferative vitreoretinopathy, cicatricial pemphigoid, surgicallyinduced fibrosis in cornea, conjunctiva and tenon

Specific Examples of the compounds of formula I include the compounds ofTable 1, below.

TABLE 1 Example Number Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

Some compounds within the scope of the invention may be prepared asdepicted in the procedures described below.

The invention is further illustrated by the following examples which areillustrative of a specific mode of practicing the invention and are notintended as limiting the scope of the claims.

Unless otherwise indicated, the following terms as used throughout thisspecification have the following meanings.

DCM refers to dichloromethane

THF refers to tetrahydrofuran

EtOAc refers to ethylacetate

“Me” refers to methyl.

“Ph” refers to phenyl.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Alkyl” refers to a straight-chain, branched or cyclic saturatedaliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons.More preferably, it is a lower alkyl of from 1 to 7 carbons, mostpreferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl andthe like. The alkyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino and SH.

“Alkoxy” refers to an “O-alkyl” group.

“Aryl” refers to an aromatic group which has at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl and biaryl groups. The aryl group may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO₂, amine,thioether, cyano, alkoxy, alkyl, and amino.

“Alkaryl” refers to an alkyl that is covalently joined to an aryl group.Preferably, the alkyl is a lower alkyl.

“Carbocyclic” refers to cyclic saturated or unsaturated aliphatichydrocarbon and aryl hydrocarbon groups wherein the ring atoms areexclusively carbons, and comprises from 6 to 20 carbon atoms, includingsaid ring atoms.

“Carbocyclic aryl” refers to an aryl group wherein the ring atoms arecarbon.

“Heterocyclic” refers to cyclic groups wherein the ring atoms comprisecarbon atoms and at least one oxygen, nitrogen, and/or sulfur atom andmay be saturated, unsaturated, i.e. have one or more double bonds, oraryl, and comprises up to 20 carbon atoms and from 1 to 5 of the aboveheteroatoms.

“Heterocyclic aryl” refers to an aryl group having from 1 to 3heteroatoms as ring atoms, the remainder of the ring atoms being carbon.Heteroatoms include oxygen, sulfur, and nitrogen.

“Hydrocarbyl” refers to a hydrocarbon radical having only carbon andhydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20carbon atoms, more preferably from 1 to 12 carbon atoms and mostpreferably from 1 to 7 carbon atoms.

“Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one ormore, but not all, of the hydrogen and/or the carbon atoms are replacedby a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radicalincluding a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g.fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, amide, ester,thioamide, thiol ester, amine, thioether, sulfonyl, etc.

“Amide” refers to —C(O)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl orhydrogen.

“Ester” refers to —C(O)—O—R′, wherein R′ is alkyl, aryl or alkylaryl.

“Thioamide” refers to —C(S)—NH—R′, wherein R′ is alkyl, aryl, alkylarylor hydrogen.

“Thiol ester” refers to —C(O)—S—R′, wherein R′ is alkyl, aryl, alkylarylor hydrogen.

“Amine” refers to a —N(R″)R′″ group, wherein R″ and R′″ areindependently selected from the group consisting of alkyl, aryl, andalkylaryl.

“Thioether” refers to —S—R″, wherein R″ is alkyl, aryl, or alkylaryl.

“Sulfonyl” refers to —S(O)₂—R″″, where R″″ is aryl, C(CN)═C-aryl, CH₂CN, alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.

Also, alternatively the substituent on the phenyl moiety may be referredto as an o, m or p substituent or a 2, 3 or 4 substituent, respectively.(Obviously, the 5 substituent is also a meta substituent and the 6substituent is an ortho substituent.)

The above compounds are evaluated for S1P2 activity according to theabove assay: The results are reported in TABLE 2, below.

Proton nuclear magnetic resonance (¹H NMR) and carbon nuclear magneticresonance (¹³C NMR) spectra were recorded on a Varian 300 or 500 MHzspectrometer in deuterated solvent. Chemical shifts were reported as δ(delta) values in parts per million (ppm) relative to tetramethylsilane(TMS) as an internal standard (0.00 ppm) and multiplicities werereported as s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet; br, broad. Data were reported in the following format:chemical shift (multiplicity, coupling constant(s) J in hertz (Hz),integrated intensity).

General Procedure A for the Synthesis of Substituted4-Isocyanatopyridine Intermediates:

Commercially available properly substituted isonicotinic acid (1.87mmol) was dissolved in THF:DCM (4:10 ml) at 0° C. Oxalyl chloride (2.0Min DCM, 1.87 ml, 3.75 mmol) was added followed by 2 drops of DMF. Theresulting solution was stirred at 0° C. for 30 min and concentrated todryness. The solid was dissolved in 10 ml of acetone and cooled to 0° C.NaN₃ (195 mg, 3.00 mmol) in 1 mL of water was added. After stirring at0° C. for 30 min, the reaction mixture was concentrated again to drynessand re-dissolved in benzene which was washed quickly with ice cold waterand dried over Na₂SO₄. The drying agent Na₂SO₄ was filtered out, and thefiltrate was stirred at 110° C. then cooled to 50° C. to generate thetitle compound in situ. This crude isocyanate was used in the subsequenttransformation without further purification.

Syntheses of5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine and(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineintermediates:

The title intermediate compounds were prepared from commerciallyavailable 3-fluoropyridine according to the following scheme.

2-(3-Fluoro-pyridin-4-yl)-propan-2-ol: 3-Fluoropyridine (11.0 g, 113.0mmol) in 100 mL of THF was treated with LDA (1.5M, 100.0 mL, 150.0 mmol)at −78° C. for 50 min under argon. Acetone (28 mL) was added and theresulting reaction mixture was stirred at −78° C. to −40° C. for 50 min.The reaction was then quenched with aqueous NH₄Cl and extracted withether. The combined organic layers were washed with H₂O and brine, thendried over Na₂SO₄ and concentrated under vacuum. Purification by MPLC(80 g column, 0 to 40% ethyl acetate in hexane as eluant) afforded thetitle compound. Spectroscopic data: ¹H-NMR (300 MHz, CDCl₃): δ ppm 1.65(s, 6 H), 7.27 (dd, J=5.57 Hz, 1 H), 8.36-8.39 (m, 2 H).

3-Fluoro-4-isopropyl-pyridine: 2-(3-Fluoro-pyridin-4-yl)-propan-2-ol(from the previous step, 6.40 g, 41.3 mmol) was dissolved in 50 mL of57% HI aqueous solution. Red phosphorus (4.48 g, 144.0 mmol) was addedand the mixture was stirred at 140° C. for 5 hours. The reaction mixturewas cooled to room temperature, neutralized with 5N aq NaOH andextracted with ether. The combined organic layers were washed with H₂Oand brine, then dried over Na₂SO₄ and concentrated under vacuum. Thetitle compound was obtained by distillation. Spectroscopic data: ¹H-NMR(300 MHz, CDCl₃): δ ppm 1.27 (d, J=7.04 Hz, 6 H), 3.25 (hept, J=7.04 Hz,1 H), 7.21 (dd, J=5.44 Hz, 1 H), 8.33-8.36 (m, 2 H).

1-(3-Fluoro-4-isopropyl-pyridin-2-yl)-ethanol:1,4-diazabicyclo[2,2,2]octane (6.16 g, 55.0 mmol) was dissolved in ether(100 mL) at −40° C. n-BuLi (2.5M in hexane, 57.50 mL, 23.0 mmol) wasadded and the resulting reaction mixture was stirred at −20° C. for 1hour. The reaction solution was then cooled to −60° C. and3-fluoro-4-isopropyl-pyridine (obtained from the previous step, 7.00 g,50.0 mmol) was introduced. The stirring was continued for 1 hour andacetaldehyde (3 mL) was added. The solution was then allowed to warm upto −30° C. in 1 hour and quenched with aqueous NH₄Cl. The aqueous layerwas extracted with ether. The combined extract was dried over Na₂SO₄ andconcentrated. Purification by MPLC (80 g column, 0 to 15% ethyl acetatein hexane as eluant) afforded the title compound. Spectroscopic data:¹H-NMR (300 MHz, CDCl₃): δ ppm 1.27 (d, J=7.04 Hz, 3 H), 1.29 (d, J=7.04Hz, 3 H), 1.50 (d, J=6.44 Hz, 3 H), 3.28 (hept, J=7.04 Hz, 1 H), 5.13(q, J=6.44 Hz, 3 H), 7.18 (dd, J=5.41 Hz, 1 H), 8.29 (d, J=5.27 Hz, 1H).

1-(3-Fluoro-4-isopropyl-pyridin-2-yl)-ethanone:1-(3-Fluoro-4-isopropyl-pyridin-2-yl)-ethanol (prepared in the previousstep, 3.00 g, 16.39 mmol) was dissolved in 60 mL of anhydrous toluene.MnO₂ (4.05 g, 46.55 mmol) was added and the resulting mixture wasstirred at 140° C. overnight. The mixture was then cooled to roomtemperature and filtered thought a pad of celite. The filtrate wasconcentrated and purified via MPLC (80 g, 0 to 20% ethyl acetate inhexane) to afford the title compound. Spectroscopic data: ¹H-NMR (300MHz, CDCl₃): δ ppm 1.28 (d, J=6.73 Hz, 6 H), 2.70 (s, 3 H), 3.35 (hept,J=6.73 Hz, 1 H), 7.38 (dd, J=5.13 Hz, 1 H), 8.39 (d, J=4.69 Hz, 1 H).

7-Isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine:1-(3-Fluoro-4-isopropyl-pyridin-2-yl)-ethanone (prepared in the previousstep, 2.50 g, 15.15 mmol) and methyl hydrazine (1.04 g, 23.00 mmol) werecombined in 8 mL of glycol. The reaction solution was stirred at 140° C.for 2 hours. After cooling, it was quenched with water, extracted withDCM, then washed with water, brine and concentrated. Columnchromatography using 15 to 35% ethyl acetate in hexane as eluantafforded the title compound as a pale yellow solid. Spectroscopic data:¹H-NMR (300 MHz, CDCl₃): δ ppm 1.39 (d, J=6.73 Hz, 6 H), 2.64 (s, 3 H),3.65 (hept, J=6.73 Hz, 1 H), 4.23 (s, 3 H), 7.14 (d, J=4.69 Hz, 1 H),8.44 (d, J=4.69 Hz 1 H).

7-Isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine 4-oxide: To7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (prepared in theprevious step, 2.50 g, 13.22 mmol) in 100 mL of chloroform was added 77%MCPBA (5.91 g, 26.44 mmol) at 0° C. The resulting solution was stirredat 90° C. for 3 hours. After cooling, it was neutralized with aq NaHCO₃and extracted with DCM thoroughly. The combined organic phases were thenwashed with water, brine and concentrated. Column chromatography using5% 7N NH₃ in MeOH/DCM as eluant afforded the title compound as a whitesolid. Spectroscopic data: ¹H-NMR (300 MHz, CDCl₃): δ ppm 1.37 (d,J=6.73 Hz, 6 H), 2.83 (s, 3 H), 3.60 (hept, J=6.73 Hz, 1 H), 4.21 (s, 3H), 6.78 (d, J=6.30 Hz, 1 H), 8.01 (d, J=6.30 Hz 1 H).

5-Chloro-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine: To asolution of 7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine 4-oxide(obtained from the previous step, 2.26 g, 11.00 mmol) in 30 mL oftoluene was added POCl₃ (3.37 g, 22.00 mmol). The resulting reactionmixture was stirred at 90° C. for 2 hours and then concentrated. DCM wasadded. The organic layer was washed with water and brine, then driedover Na₂SO₄ and concentrated. Column chromatography with DCM separatedtwo isomers and afforded the title compound as a white solid.Spectroscopic data: ¹H-NMR (300 MHz, CDCl₃): δ ppm 1.39 (d, J=6.73 Hz, 6H), 2.58 (s, 3 H), 3.62 (hept, J=6.73 Hz, 1 H), 4.21 (s, 3 H), 7.11 (s,1 H).

(7-Isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-hydrazine:5-Chloro-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (obtainedfrom the previous step, 620 mg, 2.68 mmol) and 6 mL of hydrazinemonohydrate were combined in 4 mL of EtOH. The reaction solution wasstirred at 120° C. for 3 days. The reaction solution was thenconcentrated under reduced pressure.

MeOH was added to the residue and concentrated again. Repetition of thisprocure several times until some solid formed. The solid was collectedby filtration as the title compound. Spectroscopic data: ¹H-NMR (300MHz, CDCl₃): δ ppm 1.34 (d, J=6.73 Hz, 6 H), 2.52 (s, 3 H), 3.56 (hept,J=6.73 Hz, 1 H), 4.15 (s, 3 H), 6.59 (s, 1 H).

7-Isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile: To asolution of 7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine N-oxide(obtained from the previous step, 1.06 g, 5.17 mmol) and TEA (1.08 mL,7.73 mmol) in 20 mL CH₃CN was added TMS cyanide (1.37 g, 10.34 mmol).The resulting solution was stirred at reflux for 18 hours. Another 0.5mL of TMS cyanide was added and the reaction continued for another 7hours. The solvent was removed under reduced pressure and the residuewas loaded to silica gel column and eluted with 20 to 30% ethyl acetateto afford the desired title compound as a solid. Spectroscopic data:¹H-NMR (300 MHz, CDCl₃): δ ppm 1.40 (d, J=6.74 Hz, 6 H), 2.64 (s, 3 H),3.69 (hept, J=6.74 Hz, 1 H), 4.26 (s, 3 H), 7.46 (s, 1 H).

C-(7-Isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-methylamine:

7-Isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile (fromthe previous step, 91.05 g, 5.15 mmol) was dissolved inEtOH:THF:conc.HCl (25 mL:10 mL:1.5 mL). 400 mg of 10% Pd/C was added andthe reaction mixture was stirred under hydrogen balloon overnight. Thecatalyst was filtered out and the filtrate was concentrated underreduced pressure to afford the title compound as a white solid.Spectroscopic data: ¹H-NMR (300 MHz, CD₃OD): δ ppm 1.41 (d, J=6.74 Hz, 6H), 2.56 (s, 3 H), 3.77 (hept, J=6.74 Hz, 1 H), 4.02 (s, 2 H), 4.21 (s,3 H), 7.36 (s, 1 H).

General Procedure B for the Synthesis of Substituted Ureas:

A properly substituted amine or hydrazine prepared above and a properlysubstituted isocyanate (either commercial or prepared above, 1.1 eq)were dissolved in 8 mL of THF. The reaction mixture was stirred at roomtemperature for 4 hours and the solvent was removed under reducedpressure. The title compound was isolated by column chromatography using30 to 75% ethyl acetate in hexane, further purified by recrystallizationfrom MeOH.

EXAMPLE 1

Synthesis ofN-(3,5-dichlorophenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-hydrazineprepared above and commercially available 3,5-dichlorophenyl isocyanateaccording to General procedure B described above.

N-(3,5-Dichlorophenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from 3,5-dichlorophenyl isocyanate(commercially available, 113 mg, 0.60 mmol),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 110 mg, 0.50 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.38 (d, J=6.73 Hz, 6 H), 2.44 (s, 3 H), 3.70 (hept,J=6.73 Hz, 1 H), 4.14 (s, 3 H), 6.85 (s, 1 H), 7.02 (dd, J=1.76 Hz, 1H), 7.55 (d, J=1.76 Hz, 2 H).

EXAMPLE 2

Synthesis of1-(2,6-dichloropyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineprepared above and commercially available2,6-dichloro-4-isocyanatopyridine according to General procedure Bdescribed above.

1-(2,6-Dichloropyridin-4-yl)-3-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from 2,6-dichloro-4-isocyanatopyridine(commercially available, 180 mg, 0.95 mmol),(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine(prepared above, 200 mg, 0.92 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.40 (d, J=6.73 Hz, 6 H), 2.57 (s, 3 H), 3.74 (hept,J=6.73 Hz, 1 H), 4.22 (s, 3 H), 4.61 (s, 2 H), 7.33 (s, 1 H), 7.48 (s, 2H).

EXAMPLE 3

Synthesis ofN-(2-butyl-6-chloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-hydrazineprepared above and 2-butyl-6-chloro-4-isocyanato-pyridine according toGeneral procedure B described above. Intermediate2-butyl-6-chloro-4-isocyanato-pyridine was prepared according to generalprocedure A and used in situ without further purification.

2-Butyl-6-chloro-isonicotinic acid: The titled compound was preparedfrom ethyl 2,4-dioxooctanate according to the literature reported methodin reference 1. The spectroscopic data match those reported in thereference and also reported here: ¹H-NMR (300 MHz, CD₃OD): δ ppm 0.96(t, J=7.33 Hz, 3 H), 1.33-1.43 (m, 2 H), 1.66-1.76 (m, 2 H), 2.82 (t,J=7.62 Hz, 2 H), 7.70 (s, 1 H).

2-Butyl-6-chloro-4-isocyanato-pyridine: The title compound was preparedfrom butyl-6-chloroisonicotinic acid (prepared above, 400 mg, 1.87mmol), oxalyl chloride (2.0 M in DCM, 1.87 mL, 3.75 mmol) according togeneral procedure A described above. The crude title compound was usedin the next step without further purification.

N-(2-Butyl-6-chloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from2-butyl-6-chloro-4-isocyanato-pyridine (prepared above),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 200 mg, 0.92 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 0.91 (t, J=7.32 Hz, 3 H), 126 (m , 2 H), 1.35 (d,J=6.73 Hz, 6 H), 1.61 (m, 2 H), 2.43 (s, 3 H), 2.61 (t, J=7.68 Hz, 2 H),3.65 (hept, J=6.73 Hz, 1 H), 4.12 (s, 3 H), 6.82 (s, 1 H), 7.30 (s, 1H), 7.55 (s, 1 H).

EXAMPLE 4

Synthesis ofN-(2-chloro-6-ethoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-hydrazineprepared above and 2-chloro-6-ethoxy-4-isocyanatopyridine according toGeneral procedure B described above. Intermediate2-chloro-6-ethoxy-4-isocyanatopyridine was prepared according to generalprocedure A and used in situ without further purification.

2-Chloro-6-ethoxy-isonicotinic acid: The titled compound was preparedfrom 2.6-dicloropyridine-4-carboxylic acid according to the reportedmethod in reference 2. The spectroscopic data match those reported inthe reference and also listed here ¹H-NMR (300 MHz, CD₃OD): ppm 1.38 (t,J=7.04 Hz, 3 H), 4.36 (q, J=7.04 Hz, 2 H), 7.17 (d, J=1.18 Hz, 1 H),7.39 (d, J=1.18 Hz, 1 H).

2-Chloro-6-ethoxy-4-isocyanato-pyridine: The title compound was preparedfrom 2-chloro-6-ethoxy-isonicotinic acid (prepared above), oxalylchloride (2.0 M in DCM) according to general procedure A describedabove. The crude title compound was used in the next step withoutfurther purification.

N-(2-Chloro-6-ethoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from2-chloro-6-ethoxy-4-isocyanato-pyridine (prepared above),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 180 mg, 0.82 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.33 (t, J=7.04 Hz, 3 H), 1.37 (d, J=6.73 Hz, 6 H),2.44 (s, 3 H), 3.67 (hept, J=6.73 Hz, 1 H), 4.14 (s, 3 H), 4.24 (q,J=7.04 Hz, 2 H), 6.83 (s, 1 H), 6.92 (s, 1 H), 7.10 (s, 1 H).

EXAMPLE 5

Synthesis of1-(3,5-dichlorophenyl)-3-((1,3,7-trimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(1,3,7-trimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine preparedusing the procedure described above for(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine andcommercially available 3,5-dichlorophenyl isocyanate according toGeneral procedure B described above.

1-(3,5-Dichlorophenyl)-3-((1,3,7-trimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from 3,5-dichlorophenyl isocyanate(commercially available, 170 mg, 0.90 mmol),(1,3,7-trimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine (preparedabove, 160 mg, 0.84 mmol) according to the protocols as outlined ingeneral procedure B above. Spectroscopic Data: ¹H NMR (300 MHz, CD₃OD) δppm 2.47 (s, 3 H), 2.74 (s, 3 H), 4.14 (s, 3 H), 4.47 (d, J=4.69 Hz, 2H), 7.01 (dd, J=2.07 Hz, 1 H), 7.10 (bs, 1 H), 7.21 (s, 1 H), 7.42 (d,J=2.07 Hz, 2 H), 9.45(s, 1 H).

EXAMPLE 6

Synthesis ofN-(2,6-dichloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-hydrazineprepared above and commercially available2,6-dichloro-4-isocyanatopyridine according to General procedure Bdescribed above.

N-(2,6-Dichloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from 3,5-dichlorophenyl isocyanate(commercially available, 124 mg, 0.66 mmol),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 120 mg, 0.55 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.37 (d, J=6.73 Hz, 6 H), 2.44 (s, 3 H), 3.68 (hept,J=6.73 Hz, 1 H), 4.14 (s, 3 H), 6.82 (s, 1 H), 7.63 (s, 2 H).

EXAMPLE 7

Synthesis ofN-(3,5-bis(trifluoromethyl)phenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridineprepared above and commercially available4-isocyanato-2,6-bis(trifluoromethyl)pyridine according to Generalprocedure B described above.N-(3,5-Bis(trifluoromethyl)phenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from4-isocyanato-2,6-bis(trifluoromethyl)pyridine (commercially available,117 mg, 0.44 mmol),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 80 mg, 0.36 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.38 (d, J=6.73Hz, 6 H), 2.44 (s, 3 H), 3.68 (hept,J=6.73Hz, 1 H), 4.14 (s, 3 H), 6.86 (s, 1 H), 7.53 (s, 1 H), 8.19 (s, 2H).

EXAMPLE 8

Synthesis ofN-(3-chloro-5-methoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-hydrazineprepared above and 2-chloro-6-methoxy-4-isocyanatopyridine according toGeneral procedure B described above. Intermediate2-chloro-6-methoxy-4-isocyanatopyridine was prepared according togeneral procedure A and used in situ without further purification.

N-(3-Chloro-5-methoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from2-chloro-6-methoxy-4-isocyanato-pyridine (prepared above according togeneral procedure A, crude),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 140 mg, 0.64 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.37 (d, J=6.80Hz, 6 H), 2.44 (s, 3 H), 3.69 (hept,J=6.80Hz, 1 H), 3.38 (s, 3 H), 4.14 (s, 3 H), 6.83 (s, 1 H), 6.95 (s, 1H), 7.01 (s, 1 H).

EXAMPLE 9

Synthesis of1-(2,6-dichlorophenyl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineprepared above and commercially available1,3-dichloro-5-isocyanatobenzene according to General procedure Bdescribed above.

1-(3,5-Dichlorophenyl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from 1,3-dichloro-5-isocyanatobenzene(commercially available, 188 mg, 1.0 mmol),(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine(prepared above, 200 mg, 0.92 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.40 (d, J=6.73Hz, 6 H), 2.57 (s, 3 H), 3.76 (hept,J=6.73Hz, 1 H), 4.21 (s, 3 H), 4.59 (s, 2 H), 6.99 (dd, J=1.76Hz, 1 H),7.34 (s, 1 H), 7.43 (d, J=1.76Hz, 2 H).

EXAMPLE 10

Synthesis of1-(2-chloro-6-methoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineprepared above and 2-chloro-4-isocyanato-6-methoxypyridine (preparedaccording to general procedure A described above) according to Generalprocedure B described above.

1-(2-Chloro-6-methoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from2-chloro-4-isocyanato-6-methoxypyridine (prepared above, crude, 1.0mmol),(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine(prepared above, 200 mg, 0.92 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.40 (d, J=6.73 Hz, 6 H), 2.57 (s, 3 H), 3.76 (hept,J=6.73Hz, 1 H), 4.21 (s, 3 H), 4.59 (s, 2 H), 6.82 (d, J=1.76 Hz, 1 H),7.06 (d, J=1.76 Hz, 1 H), 7.33 (s, 1 H).

EXAMPLE 11

Synthesis ofN-(2-chloro-6-propylpyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-hydrazineprepared above and 2-chloro-4-isocyanato-6-propylpyridine according toGeneral procedure B described above. Intermediate2-chloro-4-isocyanato-6-propylpyridine was prepared according to generalprocedure A and used in situ without further purification.

N-(2-Chloro-6-propylpyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from2-chloro-4-isocyanato-6-propylpyridine (prepared above),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 200 mg, 0.92 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 0.94 (t, J=7.32 Hz, 3 H), 1.37 (d, J=6.73 Hz, 6 H),1.69 (m, 2 H), 2.44 (s, 3 H), 2.61 (t, J=7.68 Hz, 2 H), 3.68 (hept,J=6.73 Hz, 1 H), 4.14 (s, 3 H), 6.84 (s, 1 H), 7.37 (s, 1 H), 7.57 (s, 1H).

EXAMPLE 12

Synthesis of1-(2-chloro-6-propylpyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineprepared above and 2-chloro-4-isocyanato-6-propylpyridine according toGeneral procedure B described above. Intermediate2-chloro-4-isocyanato-6-propylpyridine was prepared according to generalprocedure A and used in situ without further purification.

1-(2-Chloro-6-propylpyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from2-chloro-4-isocyanato-6-propylpyridine (prepared above),(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine(prepared above, 200 mg, 0.92 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 0.94 (t, J=7.32 Hz, 3 H), 1.37 (d, J=6.73 Hz, 6 H),1.69 (m, 2 H), 2.44 (s, 3 H), 2.61 (t, J=7.68 Hz, 2 H), 3.68 (hept,J=6.73 Hz, 1 H), 4.14 (s, 3 H), 6.84 (s, 1 H), 7.37 (s, 1 H), 7.57 (s, 1H).

EXAMPLE 13

Synthesis of1-(2-chloro-6-ethoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineprepared above and 2-chloro-6-ethoxy-4-isocyanatopyridine according toGeneral procedure B described above. Intermediate2-chloro-6-ethoxy-4-isocyanatopyridine was prepared according to generalprocedure A and used in situ without further purification.

1-(2-Chloro-6-ethoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from2-chloro-6-ethoxy-4-isocyanatopyridine (prepared above),(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine(prepared above, 200 mg, 0.92 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.34 (t, J=7.04Hz, 3 H), 1.39 (d, J=6.73 Hz, 6 H),2.57 (s, 3 H), 3.76 (hept, J=6.73 Hz, 1 H), 4.21 (s, 3 H), 4.25 (q,J=7.04 Hz, 2 H), 4.59 (s, 2 H), 6.78 (d, J=1.46 Hz, 1 H), 7.04 (d,J=1.46 Hz, 1 H), 7.33 (s, 1 H).

EXAMPLE 14

Synthesis of1-(2-chloro-6-propoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineprepared above and 2-chloro-4-isocyanato-6-propoxypyridine according toGeneral procedure B described above. Intermediate2-chloro-4-isocyanato-6-propoxypyridine was prepared according togeneral procedure A and used in situ without further purification.

1-(2-Chloro-6-propoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-M-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from2-chloro-4-isocyanato-6-propoxypyridine (prepared above),(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine(prepared above, 180 mg, 0.82 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.00 (t, J=7.32Hz, 3H), 1.40 (d, J=6.73 Hz, 6 H), 1.75(m, 2 H), 2.57 (s, 3 H), 3.76 (hept, J=6.73 Hz, 1 H), 4.15 (t, J=6.60Hz, 2 H), 4.21 (s, 3 H), 4.59 (s, 2 H), 6.78 (d, J=1.46 Hz, 1 H), 7.04(d, J=1.46 Hz, 1 H), 7.34 (s, 1 H).

EXAMPLE 15

Synthesis ofN-(2-chloro-6-propoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridineprepared above and 2-chloro-4-isocyanato-6-propoxypyridine according toGeneral procedure B described above. Intermediate2-chloro-4-isocyanato-6-propoxypyridine was prepared according togeneral procedure A and used in situ without further purification.

N-(3-Chloro-5-propoxyphenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from2-chloro-4-isocyanato-6-propoxypyridine (prepared above according togeneral procedure A, crude),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 160 mg, 0.73 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.00 (t, J=7.34 Hz, 3 H), 1.38 (d, J=6.73 Hz, 6 H),1.74 (m, 2 H), 2.44 (s, 3 H), 3.67 (hept, J=6.73 Hz, 1 H), 4.12-4.17 (m,5 H), 6.83 (s, 1 H), 6.94 (s, 1 H), 7.19 (s, 1 H).

EXAMPLE 16

Synthesis ofN-(2-butoxy-6-chloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridineprepared above and 2-butoxy-6-chloro-4-isocyanatopyridine according toGeneral procedure B described above. Intermediate2-butoxy-6-chloro-4-isocyanatopyridine was prepared according to generalprocedure A and used in situ without further purification.

N-(2-Butoxy-6-chloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from2-butoxy-6-chloro-4-isocyanatopyridine (prepared above according togeneral procedure A, crude),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 160 mg, 0.73 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 0.97 (t, J=7.34 Hz, 3 H), 1.38 (d, J=6.73 Hz, 6 H),1.46 (m, 2 H), 1.71 (m, 2 H), 2.44 (s, 3 H), 3.68 (hept, J=6.73 Hz, 1H), 4.14 (s, 3 H), 4.20 (t, J=6.44 Hz, 2 H), 6.83 (s, 1 H), 6.93 (s, 1H), 7.19 (s, 1 H).

EXAMPLE 17

Synthesis of1-(2-butoxy-6-chloropyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea

The title compound was generated from(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamineprepared above and 2-butoxy-6-chloro-4-isocyanatopyridine according toGeneral procedure B described above. Intermediate2-butoxy-6-chloro-4-isocyanatopyridine was prepared according to generalprocedure A and used in situ without further purification.

1-(2-Butoxy-6-chloropyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-M-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea:The title compound was obtained from2-chloro-4-isocyanato-6-propoxypyridine (prepared above),(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methanamine(prepared above, 170 mg, 0.78 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 0.97 (t, J=7.32 Hz, 3 H), 1.40 (d, J=6.73 Hz, 6 H),1.50 (m, 2 H), 1.72 (m, 2 H), 2.57 (s, 3 H), 3.76 (hept, J=6.73 Hz, 1H), 4.20 (t, J=6.44 Hz, 2 H), 4.21 (s, 3 H), 4.59 (s, 2 H), 6.80 (d,J=1.46 Hz, 1 H), 7.04 (d, J=1.46 Hz, 1 H), 7.34 (s, 1 H).

EXAMPLE 18

Synthesis ofN-(2-ethoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridineprepared above and 2-ethoxy-4-isocyanatopyridine according to Generalprocedure B described above. Intermediate 2-ethoxy-4-isocyanatopyridinewas prepared according to general procedure A and used in situ withoutfurther purification.

N-(2-Ethoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from 2-ethoxy-4-isocyanatopyridine(prepared above according to general procedure A, crude),5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 160 mg, 0.73 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.34 (t, J=7.04 Hz, 3 H), 1.38 (d, J=6.73 Hz, 6 H),2.44 (s, 3 H), 3.69 (hept, J=6.73 Hz, 1 H), 4.14 (s, 3 H), 4.24 (q,J=7.04 Hz, 2 H), 6.84 (s, 1 H), 7.04-7.07 (m, 2 H), 7.86 (d, J=6.00 Hz,1 H).

EXAMPLE 19

Synthesis ofN-(5-chloro-2,4-dimethoxyphenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide

The title compound was generated from5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridineprepared above and commercially available1-chloro-5-isocyanato-2,4-dimethoxybenzene according to Generalprocedure B described above.

N-(5-Chloro-2,4-dimethylphenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide:The title compound was obtained from1-chloro-5-isocyanato-2,4-dimethoxybenzene and5-hydrazinyl-7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine(prepared above, 160 mg, 0.73 mmol) according to the protocols asoutlined in general procedure B above. Spectroscopic Data: ¹H NMR (300MHz, CD₃OD) δ ppm 1.37 (d, J=6.73 Hz, 6 H), 2.45 (s, 3 H), 3.68 (hept,J=6.73 Hz, 1 H), 3.82 (s, 3 H), 3.85 (s, 3 H), 4.14 (s, 3 H), 6.70 (s, 1H), 6.86 (s, 1 H), 8.01 (s, 1 H).

EXAMPLE 20

Synthesis ofN-(3,5-dichlorophenyl)-2-(4-methyl-1,8-naphthyridin-2-yl)hydrazinecarboxamide

The title compound was generated from N-(pyridin-2-yl)pivalamideaccording to the chemistry described in the following scheme. Theintermediates were separated and characterized.

N-(3-Acetylpyridin-2-yl)pivalamide: To a solution ofN-(pyridin-2-yl)pivalamide (2.0 g, 11.22 mmoles) in THF at −78° C. wasadded 9.4 mL (2.1 eq) of n-BuLi. The resulting mixture was stirred at 0°C. for 3 hours. The reaction mixture was then cooled to −78° C. afterwhich N-methoxy-N-methylacetamide (1.2 g, 1.1 eq) was added as asolution in THF. The resulting mixture was stirred at room temperaturefor 2 hours. It was then quenched into ice-H₂O. The resulting mixturewas extracted with CH₂Cl₂ (3×20 mL) and the combined organic extractswere washed with H₂O (2×20 mL), brine (1×20 mL), then dried over MgSO₄.Concentration and purification by MPLC gaveN-(3-acetylpyridin-2-yl)pivalamide (1.62 g, 65%). Spectroscopic data: ¹HNMR (300 MHz, CDCl₃) δ ppm 1.36 (s, 9 H) 2.65 (s, 3 H) 7.09 (dd, J=7.76,4.83 Hz, 1 H) 8.17 (dd, J=7.76, 1.90 Hz, 1 H) 8.64 (dd, J=4.69, 2.05 Hz,1 H) 11.49 (br. s., 1 H).

tert-Butyl 3-hydroxy-3-(2-pivalamidopyridin-3-yl)butanoate: To asolution of 9.5 mL (2.1 eq) of LDA in 15 mL THF at −78° C. was added 2.0mL of t-butyl acetate (2.1 eq.). The resulting mixture was stirred at−78° C. for 30 minutes after which a solution ofN-(3-acetylpyridin-2-yl)pivalamide (1.52 g, 6.90 mmol) in THF was addedin a dropwise fashion. The resulting reaction mixture was then stirredat −78° C. for 30 minutes and was brought up to room temperature. Thereaction mixture was then quenched with saturated NH₄Cl. The resultingmixture was extracted with EtOAc (3×20 mL) and the combined organicextracts were washed with H₂O (2×20 mL), brine (1×20 mL), dried overMgSO₄ and concentrated to give the title compound (1.40 g, 61%).Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.33 (s, 9 H) 1.44 (s,9 H) 1.58 (s, 3 H) 2.65 (d, J=16.70 Hz, 1 H) 3.06 (d, J=16.70 Hz, 1 H)5.54 (s, 1 H) 6.96 (dd, J=7.76, 4.83 Hz, 1 H) 7.43 (dd, J=7.91, 1.76 Hz,1 H) 8.45 (dd, J=4.98, 1.76 Hz, 1 H) 10.29 (s, 1 H).

4-Methyl-1,8-naphthyridin-2(1H)-one: A solution of 1.3 g of tert-butyl3-hydroxy-3-(2-pivalamidopyridin-3-yl)butanoate (3.9 mmol) in 2 mL 3NHCl was microwaved at 160° C. for 5 minutes. The resulting mixture waswashed with Et₂O (2×10 mL). The aqueous layer was basified usingsaturated K₂CO₃. The precipitate formed was filtered and washed withwater to give 440 mg (71%) of the desired title compound. Spectroscopicdata: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40 (d, J=1.17 Hz, 3 H) 6.43 (s,1 H) 7.24 (dd, J=7.91, 4.69 Hz, 1 H) 8.12 (dd, J=7.91, 1.76 Hz, 1 H)8.49 (dd, J=4.69, 1.76 Hz, 1 H) 11.92 (br. s., 1 H).

2-Chloro-4-methyl-1,8-naphthyridine: To a solution of4-methyl-1,8-naphthyridin-2(1H)-one (440 mg, 2.75 mmol) in toluene wasadded 302 uL of POCl₃ (1.2 eq). The resulting mixture was refluxed at120° C. for 3 hours. After cooling to room temperature the reactionmixture was quenched into ice-H₂O and extracted with EtOAc (3×10 mL).The combined organic extracts was washed with H₂O (2×15 mL), brine (1×20mL), and then dried over MgSO₄. Concentration and purification by MPLCgave the desired 2-chloro-4-methyl-1,8-naphthyridine (330 mg, 67%).Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.72 (s, 3 H) 7.35 (d,J=1.17 Hz, 1 H) 7.53 (dd, J=8.20, 4.40 Hz, 1 H) 8.36 (dd, J=8.35, 1.90Hz, 1 H) 9.10 (dd, 1 H).

2-Hydrazinyl-4-methyl-1,8-naphthyridine: A solution of2-chloro-4-methyl-1,8-naphthyridine (330 mg, 1.8 mmol) in NH₂NH₂ wasrefluxed at 130° C. for 2 hours. The reaction mixture was cooled to roomtemperature, then excess NH₂NH₂ was removed on the rotary evaporator.The residue was taken up in 20 mL of CH₂Cl₂. The mixture was washed withsaturated NaHCO₃ (3×15 mL), brine (1×20 mL), and then dried over MgSO₄and concentrated. The residue was washed with hexane to give2-hydrazinyl-4-methyl-1,8-naphthyridine. Spectroscopic data: ¹H NMR (300MHz, CDCl₃) δ ppm 2.56 (s, 3 H) 6.66 (s, 1 H) 7.22 (dd, J=7.91, 4.40 Hz,1 H) 8.11 (dd, J=8.06, 1.90 Hz, 1 H) 8.82 (dd, 1 H).

N-(3,5-Dichlorophenyl)-2-(4-methyl-1,8-naphthyridin-2-yl)hydrazinecarboxamide:To a solution of 2-hydrazinyl-4-methyl-1,8-naphthyridine prepared above(84 mg, 0.482 mmol) in CH₂Cl₂ was added 3,5-dichlorophenyl isocyanate(91 mg, 1.0 eq). The resulting mixture was stirred at room temperatureovernight. The resulting precipitate was filtered off and washed withEtOAc to give the desired title compound. Spectroscopic data: ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.51 (s, 3 H) 6.78 (s, 1 H) 7.05 (t, J=1.90 Hz,1 H) 7.23 (dd, J=7.91, 4.40 Hz, 1 H) 7.61 (br. s., 2 H) 8.22 (dd,J=8.06, 1.90 Hz, 1 H) 8.57 (br. s., 1 H) 8.68 (dd, J=4.40, 1.76 Hz, 1 H)8.98 (s, 1 H) 9.22 (br. s., 1 H).

EXAMPLE 21

Synthesis ofN-(3,5-dichlorophenyl)-2-(4-isopropyl-1,8-naphthyridin-2-yl)hydrazinecarboxamide

The title compound was generated fromN-(3-isobutyrylpyridin-2-yl)pivalamide according to the chemistrydescribed in scheme 1 described above. The intermediates were separatedand characterized.

N-(3-Isobutyrylpyridin-2-yl)pivalamide: A solution ofN-(pyridin-2-yl)pivalamide (3.20 g, 18.0 mmol), n-BuLi (15.00 mL, 2.1eq.) and N-methoxy-N-methylisobutyramide (2.60 g, 1.1 eq) were reactedas outlined in Scheme 1 to give 3.10 g (69%) ofN-(3-isobutyrylpyridin-2-yl)pivalamide. Spectroscopic data: ¹H NMR (300MHz, CDCl₃) δ ppm 1.21 (d, J=7.03 Hz, 6 H) 1.35 (s, 9 H) 3.55 (dt,J=13.70, 6.78 Hz, 1 H) 7.08 (dd, J=7.91, 4.69 Hz, 1 H) 8.19 (dd, J=8.20,2.05 Hz, 1 H) 8.63 (dd, J=4.83, 1.90 Hz, 1 H) 11.51 (br. s., 1 H).

tert-Butyl 3-hydroxy-4-methyl-3-(2-pivalamidopyridin-3-yl)pentanoate: Asolution of N-(3-isobutyrylpyridin-2-yl)pivalamide (3.10 g, 12.5 mmol),LDA (1.5 M, 17.50 mL, 2.1 eq) and t-butyl acetate (3.5 mL, 2.1 eq) werereacted as outlined in Scheme 1 to give tert-butyl3-hydroxy-4-methyl-3-(2-pivalamidopyridin-3-yl)pentanoate which was usedin the next step without further purification.

4-Isopropyl-1,8-naphthyridin-2(1H)-one: A solution of tert-butyl3-hydroxy-4-methyl-3-(2-pivalamidopyridin-3-yl)pentanoate (3.78 g, 10.4mmol) in 12.0 mL 3N HCl were reacted as outlined in Scheme 1 to give thedesired 4-isopropyl-1,8-naphthyridin-2(1H)-one (800 mg, 41%).Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.34 (d, J=7.03 Hz, 6H) 3.34 (quin, J=6.81 Hz, 1 H) 6.66 (s, 1 H) 7.23 (dd, J=12.31, 4.10 Hz,2 H) 8.09 (dd, J=8.06, 1.61 Hz, 1 H) 8.71 (dd, J=4.69, 1.47 Hz, 1 H)11.98 (br. s., 1 H).

2-Chloro-4-isopropyl-1,8-naphthyridine: A solution of4-isopropyl-1,8-naphthyridin-2(1H)-one (800 mg, 4.3 mmol) and 475 L ofPOCl₃ in toluene were reacted as outlined in Scheme 1 to give thedesired 2-chloro-4-isopropyl-1,8-naphthyridine (690 mg, 79%).Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (d, J=6.74 Hz, 6H) 3.68 (dq, J=7.03, 6.84 Hz, 1 H) 7.38 (s, 1 H) 7.52 (dd, J=8.35, 4.25Hz, 1 H) 8.44 (dd, J=8.50, 2.05 Hz, 1 H) 9.09 (dd, 1 H).

2-Hydrazinyl-4-isopropyl-1,8-naphthyridine: A solution ofchloro-4-isopropyl-1,8-naphthyridine (690 mg, 3.4 mmol) in NH₂NH₂ wasreacted as outlined in Scheme 1 above to give the desired title compound(620 mg, 92%). Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.35(d, J=6.74 Hz, 6 H) 3.45-3.59 (m, 1 H) 6.70 (br. s., 1 H) 7.21 (dd,J=8.06, 4.54 Hz, 1 H) 8.19 (d, J=7.62 Hz, 1 H) 8.79 (br. s., 1 H).

N-(3,5-Dichlorophenyl)-2-(4-isopropyl-1,8-naphthyridin-2-yl)hydrazinecarboxamide:A 100 mg (0.5 mmol) sample of 2-hydrazinyl-4-isopropyl-1,8-naphthyridineand 94 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate were reacted asoutlined in Scheme 1 above to give the desired title compound.Spectroscopic data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.23 (d, J=6.74 Hz,6 H) 3.56 (d, J=6.74 Hz, 1 H) 6.82 (s, 1 H) 7.04 (t, J=1.76 Hz, 1 H)7.23 (dd, J=8.20, 4.40 Hz, 1 H) 7.59 (br. s., 2 H) 8.31 (d, J=1.47 Hz, 1H) 8.54 (br. s., 1 H) 8.66 (d, J=1.17 Hz, 1 H) 8.99 (br. s., 1 H) 9.25(br. s., 1 H).

EXAMPLE 22

Synthesis ofN-(3,5-dichlorophenyl)-2-(4-isopropyl-5,8-dimethylquinolin-2-yl)hydrazinecarboxamide

The title compound was generated from 2,5-dimethylaniline according tothe chemistry described in the following scheme (Scheme 2). Theintermediates were separated and characterized.

N-(2,5-Dimethylphenyl)-4-methyl-3-oxopentanamide: A mixture of2,5-dimethylaniline (7.70 g, 63.54 mmol) and ethyl4-methyl-3-oxopentanoate (10.00 g, 1.0 eq) were refluxed at 160° C.overnight. After the reaction mixture was cooled to room temperature, itwas triturated with hexane. The resulting precipitate was filtered anddried under high vacuum to yield the desiredN-(2,5-dimethylphenyl)-4-methyl-3-oxopentanamide. Spectroscopic data: ¹HNMR (300 MHz, CDCl₃) δ ppm 1.18 (d, J=7.03 Hz, 6 H) 2.30 (d, J=7.62 Hz,6 H) 2.66-2.85 (m, 1 H) 3.64 (s, 2 H) 6.87 (d, J=8.50 Hz, 1 H) 7.06 (d,J=7.62 Hz, 1 H) 7.77 (s, 1 H) 9.13 (br. s., 1 H).

4-Isopropyl-5,8-dimethylquinolin-2-ol: A sample ofN-(2,5-dimethylphenyl)-4-methyl-3-oxopentanamide and 10.0 mL of H₂SO₄was reacted at 100° C. for 1 hour. After the reaction was cooled to roomtemperature it was quenched into ice-H₂O. The resulting mixture wasextracted with CH₂Cl₂ (3×20 mL). The combined organic extracts werewashed with saturated NaHCO₃ (3×15 mL), brine (1×20 mL), dried overMgSO₄ and concentrated. The residue was recrystallized in EtOAc to give1.30 g of the desired 4-isopropyl-5,8-dimethylquinolin-2-ol.Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.29 (d, J=6.45 Hz, 6H) 2.41 (s, 3 H) 2.77 (s, 3 H) 3.84 (quin, J=6.59 Hz, 1 H) 6.67 (s, 1 H)6.93 (d, J=7.62 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 8.81 (br. s., 1 H).

2-Chloro-4-isopropyl-5,8-dimethylquinoline: A solution of4-isopropyl-5,8-dimethylquinolin-2-ol (1.30 g, 6.05 mmol), 700 L (1.2eq) of POCl₃ in toluene were reacted as outlined in Scheme 1 above toyield 1.00 g of 2-chloro-4-isopropyl-5,8-dimethylquinoline (71%).Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.34 (d, J=6.74 Hz, 6H) 2.71 (s, 3 H) 2.87 (s, 3 H) 4.12 (quin, J=6.74 Hz, 1 H) 7.21 (d,J=7.33 Hz, 1 H) 7.32 (s, 1 H) 7.40 (d, J=7.33 Hz, 1 H).

2-Hydrazinyl-4-isopropyl-5,8-dimethylquinoline: A solution of2-chloro-4-isopropyl-5,8-dimethylquinoline (1.00 g, 4.3 mmol) in NH₂NH₂was reacted as outlined in Scheme 1 above to give the title compound.Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.30 (d, J=6.74 Hz, 6H) 2.64 (s, 3 H) 2.82 (s, 3 H) 3.95-4.10 (m, 1 H) 6.72 (s, 1 H) 6.98 (d,J=7.33 Hz, 1 H) 7.30 (d, J=7.33 Hz, 1 H).

N-(3,5-Dichlorophenyl)-2-(4-isopropyl-5,8-dimethylquinolin-2-yl)hydrazinecarboxamide:A solution of 2-hydrazinyl-4-isopropyl-5,8-dimethylquinoline (100 mg,0.44 mmol) and 82 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate wasreacted as outlined in Scheme 1 above to give the desired titlecompound. Spectroscopic data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.23 (d,J=6.74 Hz, 6 H) 2.42 (s, 3 H) 2.74 (s, 3 H) 3.88-4.06 (m, 1 H) 6.89 (s,1 H) 6.94 (d, J=7.33 Hz, 1 H) 7.07 (t, J=1.90 Hz, 1 H) 7.22 (d, J=7.03Hz, 1 H) 7.65 (br. s., 2 H) 8.27 (br. s., 1 H) 8.58 (s, 1 H) 9.24 (br.s., 1 H).

EXAMPLE 23

Synthesis ofN-(3,5-dichlorophenyl)-2-(4-isopropylquinolin-2-yl)hydrazinecarboxamide

The title compound was generated from aniline according to the chemistrydescribed in the Scheme 1 and Scheme 2. The intermediates were separatedand characterized.

4-Methyl-3-oxo-N-phenylpentanamide: Aniline (5.80 g, 62.3 mmol) and 10.0g (1.0 eq.) of ethyl isobutyryl acetate were reacted as outlined inScheme 2 described above to give 6.70 g (52%) of the desired titlecompound. Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.17 (d,J=7.03 Hz, 6 H) 2.64 - 2.83 (m, 1 H) 3.61 (s, 2 H) 7.11 (t, J=7.33 Hz, 1H) 7.32 (t, J=7.91 Hz, 2 H) 7.51-7.59 (m, 2 H) 9.20 (br. s., 1 H).

4-Isopropylquinolin-2-ol: A solution of4-methyl-3-oxo-N-phenylpentanamide (3.70 g, 18.03 mmol) in 15 mL H₂SO₄was reacted as outlined in Scheme 2 above to give 1.95 g (57%) of thedesired title compound. Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δppm 1.36 (d, J=6.74 Hz, 6 H) 3.45 (quin, J=6.81 Hz, 1 H) 6.67 (s, 1 H)7.15-7.32 (m, 1 H) 7.40-7.61 (m, 2 H) 7.79 (d, J=8.50 Hz, 1 H) 12.28(br. s., 1 H).

2-Chloro-4-isopropylquinoline: 4-Isopropylquinolin-2-ol (1.95 g, 10.43mmol) and 1.14 mL (1.2 eq) of POCl₃ in toluene were reacted as outlinedin Scheme 1 above to yield 1.8 g (84%) of the desired title compound.Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.40 (d, J=6.74 Hz, 6H) 3.71 (quin, J=6.81 Hz, 1 H) 7.28 (s, 1 H) 7.48-7.63 (m, 1 H)7.65-7.78 (m, 1 H) 7.98-8.10 (m, 2 H).2-Hydrazinyl-4-isopropylquinoline: A solution of2-chloro-4-isopropylquinoline (1.80 g, 8.8 mmol) in NH₂NH₂ was reactedas outlined in Scheme 1 above to give the desired title compound.Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.41 (d, J=6.74 Hz, 6H) 3.51-3.76 (m, 1 H) 7.20-7.35 (m, 1 H) 7.44-7.60 (m, 2 H) 7.61-7.79(m, 1 H) 7.84-8.06 (m, 1 H).

N-(3,5-Dichlorophenyl)-2-(4-isopropylquinolin-2-yl)hydrazinecarboxamide:A solution of 2-hydrazinyl-4-isopropylquinoline (97 mg, 0.48 mmol) and91 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlinedin Scheme 1 above to give the desired title compound. Spectroscopicdata: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (d, J=6.74 Hz, 6 H) 3.53-3.71(m, 1 H) 6.83 (s, 1 H) 7.09 (t, J=1.90 Hz, 1 H) 7.28 (td, J=7.47, 1.46Hz, 1 H) 7.45 - 7.62 (m, 2 H) 7.69 (br. s., 2 H) 7.94 (d, J=7.62 Hz, 1H) 8.50 (br. s., 1 H) 8.70 (s, 1 H) 9.23 (br. s., 1 H).

EXAMPLE 24

Synthesis ofN-(2,6-dichloropyridin-4-yl)-2-(4,8-dimethylquinolin-2-yl)hydrazinecarboxamide

The title compound was generated from 2-chloro-4,8-dimethylquinolineaccording to the chemistry described in Scheme 1 and Scheme 2. Theintermediates were separated and characterized.

2-Hydrazinyl-4,8-dimethylquinoline: A solution of2-chloro-4,8-dimethylquinoline (1.00 g, 5.2 mmoles) in NH₂NH₂ wasreacted as outlined in Scheme 1 above to give the desired title compoundwhich was used in the next step without further purification.

N-(2,6-Dichloropyridin-4-yl)-2-(4,8-dimethylquinolin-2-yl)hydrazinecarboxamide:A solution of 2-hydrazinyl-4,8-dimethylquinoline (110 mg, 0.60 mmol) and111 mg (1.0 eq) of 2,6-dichloro-4-isocyanatopyridine was reacted asoutlined in Scheme 1 above to give the desired title compound.Spectroscopic data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50 (s, 3 H) 2.56(s, 3 H) 6.79 (s, 1 H) 7.18 (t, J=7.62 Hz, 1 H) 7.41 (d, J=7.03 Hz, 1 H)7.70 (d, J=8.20 Hz, 2 H) 8.72 (s, 2 H).

EXAMPLE 25

Synthesis ofN-(3,5-dichlorophenyl)-2-(4,8-dimethylquinolin-2-yl)hydrazinecarboxamide

The title compound was generated from 2-hydrazinyl-4,8-dimethylquinolineaccording to the chemistry described in Scheme 1. The intermediate2-hydrazinyl-4,8-dimethylquinoline was prepared according to Scheme 1and it's characterization was presented earlier (see above).

N-(3,5-Dichlorophenyl)-2-(4,8-dimethylquinolin-2-yl)hydrazinecarboxamide:A solution of 2-hydrazinyl-4,8-dimethylquinoline (100 mg, 0.53 mmol) and100 mg (1.0 eq) of 1,3-dichloro-5-isocyanatobenzene was reacted asoutlined in Scheme 1 above to give the desired title compound.Spectroscopic data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.51 (s, 3 H) 2.55(s, 3 H) 6.77-6.80 (m, 1 H) 7.09 (t, J=1.76 Hz, 1 H) 7.17 (dd, J=8.20,7.03 Hz, 1 H) 7.40 (d, J=6.74 Hz, 1 H) 7.65-7.72 (m, 3 H) 8.40 (br. s.,1 H) 8.62 (s, 1 H) 9.25 (br. s., 1 H).

EXAMPLE 26

Synthesis ofN-(2,6-dichloropyridin-4-yl)-2-(4-methylquinolin-2-yl)hydrazinecarboxamide

The title compound was generated from commercially available2-chloro-4-methylquinoline according to the chemistry described above inScheme 1. The intermediate 2-hydrazinyl-4-methylquinoline was used inthe next step without further purification.

2-Hydrazinyl-4-methylquinoline: A solution of 2-chloro-4-methylquinoline(1.00 g, 5.63 mmol) in NH₂NH₂ was reacted as outlined in Scheme 1 aboveto give the title compound which was used in the next step withoutfurther purification.

N-(2,6-Dichloropyridin-4-yl)-2-(4-methylquinolin-2-yl)hydrazinecarboxamide:A solution of 2-hydrazinyl-4-methylquinoline (100 mg, 0.58 mmol) and 110mg (1.0 eq) of 2,6-dichloro-4-isocyanatopyridine was reacted as outlinedin Scheme 1 above to give the desired title compound. Spectroscopicdata: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.57 (s, 3 H) 6.80 (s, 1 H) 7.30(t, J=7.47 Hz, 1 H) 7.50 - 7.64 (m, 2 H) 7.87 (d, J=8.20 Hz, 1 H) 8.78(s, 1 H) 8.91 (br. s., 1 H).

EXAMPLE 27

Synthesis ofN-(3,5-dichlorophenyl)-2-(4,5,8-trimethylquinolin-2-yl)hydrazinecarboxamide

The title compound was generated from 2,5-dimethylaniline according tothe chemistry described in Scheme 1 and Scheme 3 below. Theintermediates were separated and characterized.

N-(2,5-Dimethylphenyl)-3-oxobutanamide: A mixture of 2,5-dimethylaniline(1.00 g, 8.25 mmol) and ethyl 3-oxobutanoate (1.0 mL, 1.0 eq) wasmicrowaved at 180° C. for 5 minutes. After the reaction mixture wascooled to room temperature, it was triturated with hexane. The resultingprecipitate was filtered and dried under high vacuum to yield thedesired title compound. Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δppm 2.28 (s, 3 H) 2.32 (s, 3 H) 2.34 (s, 3 H) 3.63 (s, 2 H) 6.88 (d,J=7.62 Hz, 1 H) 7.07 (d, J=7.62 Hz, 1 H) 7.75 (s, 1 H) 9.00-9.12 (m, 1H).

4,5,8-Trimethylquinolin-2-ol: A 5.50 g (26.8 mmol) sample ofN-(2,5-dimethylphenyl)-3-oxobutanamide in 10.0 mL of H₂SO₄ wasmicrowaved at 140° C. for 5 minutes. After the reaction was cooled toroom temperature it was quenched into ice-H₂O. The resulting mixture wasbasified with saturated NaHCO₃. The resulting mixture was extracted withCH₂Cl₂ (3×20 mL) and the combined organic extracts were washed with H₂O(1×15 mL), brine (1×20 mL), dried over MgSO₄ and concentrated to givethe desired title compound (1.4 g, 28%). Spectroscopic data: ¹H NMR (300MHz, CDCl₃) δ ppm 2.41 (s, 3 H) 2.69 (d, J=1.17 Hz, 3 H) 2.73 (s, 3 H)6.48 (s, 1 H) 6.90 (d, J=7.33 Hz, 1 H) 7.19 (d, J=7.62 Hz, 1 H) 8.87(br. s., 1 H).

2-Chloro-4,5,8-trimethylquinoline: A solution of4,5,8-trimethylquinolin-2-ol (2.40 g, 12.8 mmol) and 1.4 mL (1.2 eq) ofPOCl₃ in toluene was reacted as outlined in Scheme 1 above to yield thedesired title compound (2.2 g, 85%). Spectroscopic data: ¹H NMR (300MHz, CDCl₃) δ ppm 2.68 (s, 3 H) 2.82 (s, 3 H) 2.85 (s, 3 H) 7.12 (s, 1H) 7.18 (d, J=7.33 Hz, 1 H) 7.39 (d, 1 H).

2-Hydrazinyl-4,5,8-trimethylquinoline: A solution of2-chloro-4,5,8-trimethylquinoline (2.2 g, 10.7 mmoles) in NH₂NH₂ wasreacted as outlined in Scheme 1 above to give the desired title compound(830 mg, 38%). Spectroscopic data: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.62(s, 3 H) 2.78 (s, 6 H) 4.13 (br. s., 2 H) 5.74 (br. s., 1 H) 6.52 (s, 1H) 6.95 (d, J=7.03 Hz, 1 H) 7.28 (d, 1 H).

N-(3,5-Dichlorophenyl)-2-(4,5,8-trimethylquinolin-2-yl)hydrazinecarboxamide:A solution of 2-hydrazinyl-4,5,8-trimethylquinoline (100 mg, 0.50 mmol)and 93.53 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted asoutlined in Scheme 1 above to give the desired title compound.Spectroscopic data: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.43 (s, 3 H) 2.73(s, 3 H) 2.77 (s, 3 H) 6.69 (s, 1 H) 6.92 (d, J=7.03 Hz, 1 H) 7.09 (t,J=1.90 Hz, 1 H) 7.23 (d, J=7.62 Hz, 1 H) 7.68 (br. s., 2 H) 8.35 (s, 1H) 8.53 (s, 1 H) 9.24 (br. s., 1 H).

TABLE 2 FLIPR Object EC50 (nM)/(% Antagonism) ID S1P₁ S1P₂ S1P₃ 1 >830047 (96) >8300 2.9 (33P S1P) 2 >8300 118 (91) >8300 23.8 (33P S1P)3 >8300 8 (99) >8300 5.7 (33P S1P) 4 >8300 1.5 (33P S1P) >8300 5 >8300135 (82) >8300 6 >8300 11 (95) >8300 2.2 (33P S1P) 7 >8300 196(98) >8300 8 >8300 12 (99) >8300 6.4 (33P S1P) 9 >8300 149 (52) >830026.4 (33P S1P) 10 >8300 58 (98) >8300 9.9 (33P S1P) 11 >8300 9(98) >8300 5 (33P S1P) 12 >8300 24 (99) >8300 2.1 (33P S1P) 13 >8300 0.5(33P S1P) >8300 14 >8300 0.5 (33P S1P) >8300 15 >8300 0.2 (33PS1P) >8300 16 >8300 0.1 (33P S1P) >8300 17 >8300 0.1 (33P S1P) >830018 >8300 266 (33P S1P) >8300 19 >8300 40 (33P S1P) >8300 20 >8300 196(33P S1P) >8300 21 >8300 81 (33P S1P) >8300 22 >8300 199 (33P S1P) >830023 >8300 188 (33P S1P) >8300 24 >8300 390 (33P S1P) >8300 25 >8300 451(33P S1P) >8300 26 >8300 196 (33P S1P) >8300 27 >8300 386 (33P S1P)>8300

As can be seen from the above results, the pyrazolopyridinyl compoundsof this invention are preferred over the benzopyridinyl or pyridopyridinyl compounds. In particular, the pyrazolopyridinyl compoundswhich comprise substituted aryl which is pyridinyl are especiallypreferred. And finally, the pyrazolopyridinyl compounds which comprisesubstituted aryl which is pyridinyl and wherein the substitution patternis o-halo, o-alkyloxy, more preferably o-chloro, o-ethyloxy, propyloxyor butyloxy are most preferred.

As a result of the above activity of the compounds utilized in themethod of the present invention, it is clear that such compounds may beused in treating and/or preventing the following diseases and conditionsof the eye as well as other diseases and conditions discussed below. (Itshould be noted that “treating” means ameliorating and/or modulating adisease or disorder that exists in a subject (whether the subject isaware of the disease or disorder or not) or delaying the onset of thedisease or disorder and “preventing” means preventing the recurrence,onset or development of one or more symptoms of a disease or disorder ina subject by administering one or more compounds of the invention.)

Ocular diseases; wet and dry age-related macular degeneration, diabeticretinopathy, retinopathy of prematurity, geographic atrophy,glaucomatous optic neuropathy

Systemic vascular barrier related diseases;, various inflammatorydiseases, including acute lung injury, its prevention, sepsis, tumormetastasis, atherosclerosis, pulmonary edemas, and ventilation-inducedlung injury

Allergies and other inflammatory diseases; urticaria, bronchial asthma,and other airway inflammations including pulmonary emphysema and chronicobstructive pulmonary diseases

Cardiac protection; Ischemia/reperfusion injury, atherosclerosis

Anti-fibrosis; ocular, cardiac, hepatic and pulmonary fibrosis,proliferative vitreoretinopathy, cicatricial pemphigoid, surgicallyinduced fibrosis in cornea, conjunctiva and tenon

Pains and anti-inflammation; Acute pain, flare-up of chronic pain,musculo-skeletal pains, visceral pain, pain associated with diabeticneuropathy, rheumatoid arthritis, chronic knee and joint pain,tendonitis, osteoarthritis, bursitis, neuropathic pains

Wound Healing; scar-free healing of wounds from cosmetic skin surgeryand ocular surgery, GI surgery, general surgery, various mechanical andheat injuries

See, for example, the following articles:

-   -   1. Hla, Timothy “Inhibitor of the Receptor Activity of the S1P2        Receptor for Inhibiting Pathological Angiogenesis in the eye.”        PCT Int. Appl. (2008), 54 pp. WO 2008154470 A1    -   2. Athanasia Skoura, Teresa Sanchez, Kevin Claffey, Suzanne M.        Mandala, Richard L. Proia, and Timothy Hla “Essential role of        sphingosine 1-phosphate receptor 2 in pathological angiogenesis        of the mouse retina.” J Clin Invest. 2007 Sep. 4; 117(9):        2506-2516.    -   3. Serriere-Lanneau V, Teixeira-Clerc F, Li L, et al. The        sphingosine 1-phosphate receptor S1P2 triggers hepatic wound        healing. FASEB J 2007 21:2005-13.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. Thus, however detailed the foregoing may appearin text, it should not be construed as limiting the overall scopehereof; rather, the ambit of the present invention was to be governedonly by the lawful construction of the appended claims. In particular,the present invention includes, as preferred novel compounds, havingsubtype-selective modulating activity of sphingosine-1-phosphate-2(SIP₂) receptors, compounds selected from the group consisting of1-(2-chloro-6-loweralkyloxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)ureasand1-(2-chloro-6-loweralkyloxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)imino)ureas.

1. Compounds represented by the formula I having sphingosine-1-phosphatereceptor antagonist biological activity:

wherein: wherein A is a direct bond or (CR) and B, C and D areindependently selected from the group consisting of (CR) and N, whereinR is H or alkyl, provided however, not all, of B, C and D are N and,when A is a direct bond, D is (CR); R³ is selected from the groupconsisting of alkyl: X is selected from the group consisting of O, NR⁴and CR⁴R⁵, wherein R⁴ and R⁵ are independently selected from the groupconsisting of H and alkyl, Y is selected from the group consisting of Oor S and Z is a substituted aryl ring.
 2. A compound represented by theformula II, or a pharmaceutically acceptable salt thereof:

wherein R¹ and R² are independently selected from the group consistingof H and alkyl, methoxy, hydroxyl, halogen, nitrile, andtrifluoromethyl; R³ is independently selected from the group consistingof alkyl, methoxy, hydroxyl, halogen, nitrile, and trifluoromethyl; D isCR or N; R is H or alkyl; X is O, NR⁴, CR⁴R⁵, where R⁴ and R⁵ areindependently selected from the group consisting of H and alkyl, e.g.lower alkyl and may have from 1 to 10 carbons, and may be cyclic orbranched chain alkyl having 3 to 10 carbons, methoxy, hydroxyl, F, Br,I, nitrile, and trifluoromethyl; Y is O or S, Z is a substituted arylring, having the following structure:

wherein R⁶ and R⁷ are independently selected from the group consistingof alkyl and may include from 1 to 10 carbons, and may be cyclic orbranched chain alkyl having 3 to 10 carbons, methoxy, hydroxyl, halogen,nitrile, and trifluoromethyl, and E is N or CR.
 3. The compound of claim2 wherein R¹, R² and R³ are independently H, halogen, methyl, orisopropyl; X is NR⁴; R⁴ is H: Y is O; R⁶ and R⁷ are independently H orchloro; E is N or CR; and R is H. 4.-14. (canceled)
 15. The compound ofclaim 2 wherein said compound is selected from the group consisting ofN-(3,5-dichlorophenyl)-2-(4-methyl-1,8-naphthyridin-2-yl)hydrazinecarboxamide,N-(3,5-dichlorophenyl)-2-(4-isopropyl-1,8-naphthyridin-2-yl)hydrazinecarboxamide,N-(3,5-dichlorophenyl)-2-(4-isopropyl-5,8-dimethylquinolin-2-yl)hydrazinecarboxamide,N-(3,5-dichlorophenyl)-2-(4-isopropylquinolin-2-yl)hydrazinecarboxamide,N-(2,6-dichloropyridin-4-yl)-2-(4,8-dimethylquinolin-2-yl)hydrazinecarboxamide,N-(3,5-dichlorophenyl)-2-(4,8-dimethylquinolin-2-yl)hydrazinecarboxamide,N-(2,6-dichloropyridin-4-yl)-2-(4-methylquinolin-2-yl)hydrazinecarboxamideandN-(3,5-dichlorophenyl)-2-(4,5,8-trimethylquinolin-2-yl)hydrazinecarboxamide16. A compound represented by the formula III, or a pharmaceuticallysalt thereof:

wherein R¹ and R² are independently selected from the group consistingof H and alkyl, methoxy, hydroxyl, halogen, nitrile, andtrifluoromethyl; R³ is independently selected from the group consistingof alkyl, methoxy, hydroxyl, halogen, nitrile, and trifluoromethyl; X isO, NR⁴, CR⁴R⁵, where R⁴ and R⁵ are independently selected from the groupconsisting of H and alkyl, e.g. lower alkyl and may have from 1 to 10carbons, and may be cyclic or branched chain alkyl having 3 to 10carbons, methoxy, hydroxyl, F, Br, I, nitrile, and trifluoromethyl; Y isO or S; R is H, methoxy or alkyl; Z is a substituted aryl ring, havingthe following structure:

wherein R⁶ and R⁷ are independently selected from the group consistingof alkyl and may include from 1 to 10 carbons, and may be cyclic orbranched chain alkyl having 3 to 10 carbons, methoxy, ethoxy, hydroxyl,halogen, nitrile, and trifluoromethyl; and E is N or CR.
 17. Thecompound of claim 16 wherein R¹, R² and R³ are independently methyl orisopropyl; X is NR⁴ or CR⁴R⁵; R⁴ is H; R⁵ is H; Y is O; R⁶ and R⁷ areindependently selected from the group consisting of alkyl and mayinclude from 1 to 5 carbons, methoxy, ethoxy, chloro andtrifluoromethyl; E is N or CR; and R is H or methoxy. 18.-28. (canceled)29. The compound of claim 16 wherein said compound is selected from thegroup consisting ofN-(3,5-dichlorophenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,1-(2,6-dichloropyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,N-(2-butyl-6-chloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,N-(2-chloro-6-ethoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,1-(3,5-dichlorophenyl)-3-((1,3,7-trimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,N-(2,6-dichloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,N-(3,5-bis(trifluoromethyl)phenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,N-(3-chloro-5-methoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,1-(2,6-dichlorophenyl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,1-(2-chloro-6-methoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,N-(2-chloro-6-propylpyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,1-(2-chloro-6-propylpyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,-(2-chloro-6-ethoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,1-(2-chloro-6-propoxypyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,N-(2-chloro-6-propoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,N-(2-butoxy-6-chloropyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide,1-(2-butoxy-6-chloropyridin-4-yl)-3-((7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)methyl)urea,N-(2-ethoxypyridin-4-yl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamideandN-(5-chloro-2,4-dimethoxyphenyl)-2-(7-isopropyl-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazinecarboxamide.30-32. (canceled)
 33. A method of treating a disease of a mammalselected from the group consisting of ocular diseases; systemic vascularbarrier related diseases; allergies and other inflammatory diseases;cardiac diseases or conditions; fibrosis; pain and wounds whichcomprises administering to a patient in need thereof a compoundaccording to claim 2 represented by the general formula II

wherein R¹ and R² are independently selected from the group consistingof H and alkyl, methoxy, hydroxyl, halogen, nitrile, and trifluoromethylR³ is independently selected from the group consisting of alkyl,methoxy, hydroxyl, halogen, nitrile, and trifluoromethyl; D is CR or N;R is H or alkyl; X is O, NR⁴, CR⁴R⁵, where R⁴ and R⁵ are independentlyselected from the group consisting of H and alkyl, e.g. lower alkyl andmay have from 1 to 10 carbons, and may be cyclic or branched chain alkylhaving 3 to 10 carbons, methoxy, hydroxyl, F, Br, I, nitrile, andtrifluoromethyl; Y is O or S Z is a substituted aryl ring, having thefollowing structure:

wherein R⁶ and R⁷ are independently selected from the group consistingof alkyl and may include from 1 to 10 carbons, and may be cyclic orbranched chain alkyl having 3 to 10 carbons, methoxy, hydroxyl, halogen,nitrile, and trifluoromethyl; and E is N or CR.
 34. (canceled)
 35. Apharmaceutical composition useful for treating or preventing diseasesand conditions selected from the group consisting of ocular diseases;systemic vascular barrier related diseases; allergies and otherinflammatory diseases; cardiac diseases or conditions; fibrosis; painand wounds which comprises a compound according to claim 2 incombination with a pharmaceutically acceptable carrier. 36.-42.(canceled)
 43. A method of treating a disease of a mammal selected fromthe group consisting of ocular diseases; systemic vascular barrierrelated diseases; allergies and other inflammatory diseases; cardiacdiseases or conditions; fibrosis; pain and wounds which comprisesadministering to a patient in need thereof a compound according to claim16 represented by the general formula III:

wherein R¹ and R² are independently selected from the group consistingof H and alkyl, methoxy, hydroxyl, halogen, nitrile, andtrifluoromethyl; R³ is independently selected from the group consistingof alkyl, methoxy, hydroxyl, halogen, nitrile, and trifluoromethyl; X isO, NR⁴, CR⁴R⁵, where R⁴ and R⁵ are independently selected from the groupconsisting of H and alkyl, e.g. lower alkyl and may have from 1 to 10carbons, and may be cyclic or branched chain alkyl having 3 to 10carbons, methoxy, hydroxyl, F, Br, I, nitrile, and trifluoromethyl; Y isO or S; R is H, methoxy or alkyl; Z is a substituted aryl ring, havingthe following structure:

wherein R⁶ and R⁷ are independently selected from the group consistingof alkyl and may include from 1 to 10 carbons, and may be cyclic orbranched chain alkyl having 3 to 10 carbons, methoxy, ethoxy, hydroxyl,halogen, nitrile, and trifluoromethyl; and E is N or CR.
 44. Apharmaceutical composition useful for treating or preventing diseasesand conditions selected from the group consisting of ocular diseases;systemic vascular barrier related diseases; allergies and otherinflammatory diseases; cardiac diseases or conditions; fibrosis; painand wounds which comprises a compound according to claim 16 incombination with a pharmaceutically acceptable carrier.